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【结 构 式】 
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【分子编号】19346 【品名】1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid 【CA登记号】157688-46-5 |
【 分 子 式 】C12H21NO4 【 分 子 量 】243.30308 【元素组成】C 59.24% H 8.7% N 5.76% O 26.3% |
合成路线1
该中间体在本合成路线中的序号：(III)4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2. After protection of (II) as the N-Boc derivative (III), reduction of its carboxylate group with borane in THF provided alcohol (IV). Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V). This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI), which was further hydrogenated to (VII) in the presence of Pd/C. After saponification of the methyl ester function of (VII), the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF. Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. Then, alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).
| 【1】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 . |
| 【2】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 . |
| 【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17883 | 2-(4-pyridinyl)acetic acid | 28356-58-3 | C7H7NO2 | 详情 | 详情 |
| (II) | 45854 | 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid | 51052-78-9 | C7H13NO2 | 详情 | 详情 |
| (III) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (IV) | 43453 | tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate | C12H23NO3 | 详情 | 详情 | |
| (V) | 59541 | tert-butyl 4-(2-oxoethyl)-1-piperidinecarboxylate | C12H21NO3 | 详情 | 详情 | |
| (VI) | 45855 | tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (VII) | 45856 | tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 59542 | tert-butyl 4-(4-hydroxybutyl)-1-piperidinecarboxylate | C14H27NO3 | 详情 | 详情 | |
| (IX) | 59543 | tert-butyl 4-(4-bromobutyl)-1-piperidinecarboxylate | C14H26BrNO2 | 详情 | 详情 | |
| (X) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (XI) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Intermediate (VII) can be obtained by following two different pathways: 1. Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X), which is then protected with Boc2O and NaOH in THF to yield (XI). Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII), which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2, followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM), to provide crotonate (XIV). Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV), which is finally hydrolyzed with NaOH in MeOH. 2. Alternatively, intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII), which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX). Finally, (XIX) is protected by reaction with Boc2O and NaOH in THF.
| 【1】 Molino, B.F.; Klein, S.I.; Czekaj, M.; et al.; Design of a new class of orally active fibrinogen receptor antagonists. J Med Chem 1998, 41, 14, 2492. |
| 【2】 Klein, S.I.; Molino, B.F. (Aventis Pharma SA); Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides. EP 0812205; JP 1997507213; US 5866685; WO 9510295 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 45852 | 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid | C14H25NO4 | 详情 | 详情 | |
| (IX) | 17883 | 2-(4-pyridinyl)acetic acid | 28356-58-3 | C7H7NO2 | 详情 | 详情 |
| (X) | 45854 | 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid | 51052-78-9 | C7H13NO2 | 详情 | 详情 |
| (XI) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (XII) | 43453 | tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate | C12H23NO3 | 详情 | 详情 | |
| (XIII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XIV) | 45855 | tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (XV) | 45856 | tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate | C15H27NO4 | 详情 | 详情 | |
| (XVI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XVII) | 45857 | 4-vinylpyridine | C7H7N | 详情 | 详情 | |
| (XVIII) | 45858 | diethyl 2-[2-(4-pyridinyl)ethyl]malonate | C14H19NO4 | 详情 | 详情 | |
| (XIX) | 45859 | 4-(4-piperidinyl)butyric acid | C9H17NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (II) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with N-Boc-piperidineacetic acid (VII) using EDC and HOBt yielded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, piperidine (IX) was condensed with trimethylsilyl isocyanate to produce the corresponding urea. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.
| 【1】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890. |
| 【2】 Bishop, W.R.; Girijavallabhan, V.M.; Njoroge, F.G.; Bryant, M.S.; Nomeir, A.A.; Doll, R.J.; Ganguly, A.K.; Kirschmeier, P.; Liu, M.; Vibulbhan, B.; Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity. Bioorg Med Chem 1999, 7, 5, 861. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19976 | isocyanato(trimethyl)silane; trimethylsilyl isocyanate | C4H9NOSi | 详情 | 详情 | ||
| (I) | 19338 | ethyl 4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H22BrClN2O2 | 详情 | 详情 | |
| (II) | 19340 | ethyl 4-(3-bromo-8-chloro-9-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21BrClN3O4 | 详情 | 详情 | |
| (III) | 19341 | ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H23BrClN3O2 | 详情 | 详情 | |
| (IV) | 19342 | ethyl 4-(9-amino-3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H22Br2ClN3O2 | 详情 | 详情 | |
| (V) | 19343 | ethyl 4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21Br2ClN2O2 | 详情 | 详情 | |
| (VI) | 19344 | 3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H17Br2ClN2 | 详情 | 详情 | |
| (VII) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (VIII) | 25662 | tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate | C31H36Br2ClN3O3 | 详情 | 详情 | |
| (IX) | 25663 | 1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone | C26H28Br2ClN3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Introduction of a bromine atom at the 10-position of the benzocycloheptapyridine (I) was achieved by the following sequence. Nitration of (I) using NaNO3-H2SO4 afforded a mixture of nitro compounds (II) and (III), from which the major 9-nitro isomer (III) was separated by silica gel chromatography. Reduction of the nitro group of (III) with iron filings and CaCl2 in refluxing aqueous ethanol gave amine (IV), which was brominated at position 10 with Br2 in AcOH. The brominated aniline (VI) was then deaminated by diazotization, followed by reduction of the resulting diazonium salt with hypophosphorous acid to give trihalo compound (VI). Hydrolysis of carbamate group of (VI) in boiling concentrated HCl afforded piperidine (VII). Subsequent reduction of the C-11 double bond of (VII) was carried out using DIBAL-H in refluxing toluene to afford the corresponding racemic piperidine. Separation of enantiomers was achieved by HPLC on a ChiralPak AD column or by chemical resolution using N-acetyl-L-phenylalanine as the resolving agent. The appropriate R-(+) enantiomer (VIII) was coupled with N-Boc-piperidylacetic acid (IX) in the presence of EDC and HOBt to yield protected amide (X). Hydrolysis of the Boc protecting group was performed with trifluoroacetic acid, and the resulting piperidine (XI) was finally treated with trimethylsilyl isocyanate to give the desired carboxamide (3-5).
| 【1】 Sorbera, L.A.; Castañer, J.; Lonafarnib. Drugs Fut 2003, 28, 12, 1168. |
| 【2】 Mallams, A.K. (Schering Corp.); Method for preparing substituted 1-piperidinecarboxamide derivatives. WO 9804549 . |
| 【3】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890. |
| 【4】 Doll, R.J.; Kelly, J.M.; Njoroge, F.G.; Mallams, A.K.; Remiszewski, S.W.; Taveras, A.G. (Schering Corp.); Tricyclic amides useful for inhibition of G-protein function and for treatment of proliferative diseases. EP 1019392; EP 1380581; JP 1999501671; WO 9723478 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 19338 | ethyl 4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H22BrClN2O2 | 详情 | 详情 | |
| (II) | 19339 | ethyl 4-(3-bromo-8-chloro-7-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21BrClN3O4 | 详情 | 详情 | |
| (III) | 19340 | ethyl 4-(3-bromo-8-chloro-9-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21BrClN3O4 | 详情 | 详情 | |
| (IV) | 19341 | ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H23BrClN3O2 | 详情 | 详情 | |
| (V) | 19342 | ethyl 4-(9-amino-3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H22Br2ClN3O2 | 详情 | 详情 | |
| (VI) | 19343 | ethyl 4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | C22H21Br2ClN2O2 | 详情 | 详情 | |
| (VII) | 19344 | 3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H17Br2ClN2 | 详情 | 详情 | |
| (VIII) | 19345 | (11R)-3,10-dibromo-8-chloro-11-(4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H19Br2ClN2 | 详情 | 详情 | |
| (IX) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (X) | 19347 | tert-butyl 4-(2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl)-1-piperidinecarboxylate | C31H38Br2ClN3O3 | 详情 | 详情 | |
| (XI) | 19348 | 1-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone | C26H30Br2ClN3O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Amine (VII) is coupled to N-Boc-4-piperidineacetic acid (VIII) by means of EDC/HOBt to afford amide (IX). Subsequent acidic cleavage of the N-Boc group of (IX) leads to amine (X) (1,2). Piperidine (X) is finally coupled with malonic acid mono-amide (XI) to furnish the title compound (1,2). In a related method, piperidine (X) is coupled to mono-methyl malonate (XII), yielding the amide ester (XIII). Basic hydrolysis of the methyl ester group of (XIII) then leads to the sodium carboxylate salt (XIV), which is finally reacted with ammonium chloride in the presence of EDC/HOBt to produce the target amide (3).
| 【1】 Njoroge, F.G.; Vibulbhan, B.; Pinto, P.; Strickland, C.L.; Bishop, W.R.; Kirschmeir, P.; Girijavallabhan, V.; Ganguly, A.K.; Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase. Bioorg Med Chem 2003, 11, 1, 139. |
| 【2】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. US 6030982 . |
| 【3】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. WO 9830558 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 19345 | (11R)-3,10-dibromo-8-chloro-11-(4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H19Br2ClN2 | 详情 | 详情 | |
| (VIII) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (IX) | 19347 | tert-butyl 4-(2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl)-1-piperidinecarboxylate | C31H38Br2ClN3O3 | 详情 | 详情 | |
| (X) | 19348 | 1-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone | C26H30Br2ClN3O | 详情 | 详情 | |
| (XI) | 63973 | 3-oxo-beta-alanine | C3H5NO3 | 详情 | 详情 | |
| (XII) | 16198 | 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester | 16695-14-0 | C4H6O4 | 详情 | 详情 |
| (XIII) | 63971 | methyl 3-[4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl}-2-oxoethyl)-1-piperidinyl]-3-oxopropanoate | C30H34Br2ClN3O4 | 详情 | 详情 | |
| (XIV) | 63972 | sodium 3-[4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl}-2-oxoethyl)-1-piperidinyl]-3-oxopropanoate | C29H31Br2ClN3NaO4 | 详情 | 详情 |